Stereotactic body radiation therapy-based treatmentmodel for stage I medically inoperable small celllung cancerGregory M.M. Videtic MD, CM a,⁎, Kevin L. Stephans MD a,Neil M. Woody MD a, Nathan A. Pennell MD, PhD b, Marc Shapiro MD b,Chandana A. Reddy MS a, Toufik Djemil PhD a
aDepartment of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OhiobDepartment of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
Received 13 August 2012; revised 1 October 2012; accepted 2 October 2012
Presented in part at the 14th World Conference on Lung Cancer (WCLC 2011), July 3-7, 2011, Amsterdam, The Netherlands.Conflicts of interest: None.⁎ Corresponding author. Cleveland Clinic Lerner College of Medicine, Staff Physician, Department of Radiation Oncology, Cleveland Clinic, 9500
302 G.M.M. Videtic et al Practical Radiation Oncology: October-December 2013
Introduction
Small cell lung cancer (SCLC) represents approximately15% of all lung cancer cases diagnosed in the United States.1
Of these, about 30% of SCLC patients present with limiteddisease (LD).1 Concurrent chemoradiation therapy followedby prophylactic cranial irradiation is used for the curativemanagement of LD-SCLC and results in a median survivalof 23 months and a 5-year survival rate of 26%.2 There is asmall subset of LD-SCLC patients (5%-15%) who presentwith disease limited to the lung, without regional nodalinvolvement (T1/T2N0, or stage I).3 Patients with thislocalized SCLC are managed like their counterparts with theequivalent stage of non-small cell lung cancer (NSCLC), inthat they undergo surgical resection of the lung lesion alongwith a mediastinal nodal dissection since their overallprognosis is felt to be the best with this approach.4 However,unlike NSCLC patients, medically fit resected stage I SCLCpatients are routinely offered adjuvant chemotherapy,followed by prophylactic cranial irradiation (PCI).1
Regarding surgical resection, a significant proportion ofearly-stage NSCLC patients presents with impairedcardiopulmonary reserve, placing them at increased riskof perioperative complications and long-term disabilitywith standard anatomic resections; these patients aredeemed medically inoperable.5 Over the past decade,stereotactic body radiation therapy (SBRT) has emerged asa novel radiation modality with significant applications inthe medically inoperable, early-stage NSCLC population.6
For this population SBRT consistently provides excellentlocal control, little acute toxicity, and improved overallsurvival compared to historic results seen with conven-tional fractionated radiation therapy.6 The same phenom-enon of medical inoperability is also occasionally seen withearly-stage SCLC patients. In that respect, since initiatingan SBRT lung program at our Institute in 2004 we haveemployed this technology in the care of such patients.Inasmuch as this is a rare disease presentation, we decidedto report the outcomes for our series, albeit small, ofmedically inoperable early-stage SCLC patients becausewe believe it further characterizes the role and utility ofSBRT in thoracic malignancies and describes the feasibil-ity of integrating the other recognized SCLC treatmentmodalities, chemotherapy, and PCI into the care of poorrisk patients, since there is no standardized approach.
Figure 1 Representative axial computed tomographic imagesof the chest for an early-stage small cell lung cancer (arrow). (A)Prior to SBRT; (B) 4-months post SBRT; (C) 23-months postSBRT, demonstrating the evolving fibrotic response. SBRT,stereotactic body radiation therapy.
Methods and materials
A survey of our institutional review board approvedSBRT data registry for the period 2004-2010 revealed 6cases out of 430 patients (1.4%) diagnosed with stage I(American Joint Committee on Cancer 6th edition7) SCLC.All patients had biopsy proven disease. Medical inoper-ability was established by an experienced thoracic surgeon.
All patients were staged using computed tomography (CT)of the chest, abdomen and pelvis, magnetic resonanceimaging of the brain and positron emission tomography(PET). Mediastinoscopy was not required but any abnormalmediastinal nodes on PETwere expected to be characterizedby a bronchoscope-guided ultrasound approach.
The institutional approach to SBRT has been previouslydescribed.8–10 In brief, patients were treated on a Novalis-
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BrainLAB system (BrainLab, Westchester, IL) using avacuum bag restriction system (Bodyfix; Medical Intelli-gence Inc, Phoenix, AZ) and an abdominal compressiondevice to limit the maximum range of tumor motion to b1cm in all directions. Treatment planning was carried outwith BrainLAB planning software and referenced to thefree-breathing study. Patient setup and target localizationwere verified daily prior to delivery using the ExacTracimage-guidance system (BrainLAB). Dose schedules wereselected at the treating physician's discretion and reflectedtumor location, distinguishing “peripheral” from “central”tumors per the criteria of RTOG 0236.11
The timing of chemotherapy with respect to SBRT wasat the discretion of the treating medical oncologist, withthe expectation that the patient would receive 4 cycles of aplatinum agent with etoposide every 3 weeks. Oncompletion of SBRT and chemotherapy, PCI (25 Gy/10fractions) was planned once the patient had demonstratedresponse in the chest and had reimaging of the brain forrestaging. First follow-up was generally 6 to 8 weeks aftercompletion of PCI, with same-day pulmonary functiontests and chest CT. Thereafter, routine follow-up wasevery 3 months with CT imaging at each visit andpulmonary function tests twice yearly.
Toxicity was assessed according to the CommonTerminology Criteria for Adverse Events, version 3.0.12
Local failure was defined as progressive and increasing CTscan abnormalities confirmed by progressive and incre-mental increases in a lesion's standardized uptake values(SUVs) on serial PET imaging, with or without biopsy.Nodal failure was defined as radiographic (PET or CT)
Table 1 Patient, tumor, and treatment characteristics of medically
Patientno.
Sex Age KPS Inoperable—reason
Inoperable—details
SmokeratSBRT
1 M 57 50 Vascular CHF, MI, activePVD withamputation
No
2 F 68 80 Pulmonary FEV1 46% pred.DLCO 20% pred.
Yes
3 F 63 80 Pulmonary FEV1 17% pred.DLCO 24% pred.
No
4 M 68 90 Pulmonary FEV1 46% pred.requiringpneumonectomy
No
5 F 73 90 Cardiac Acute ischemiaduringmed'scopy
No
6 F 72 90 Pulmonary FEV1 25% pred.DLCO 40% pred.
No
BMI, body mass index; “Central”, tumor location per Radiation Therapy OncCpE, carboplatin-etoposide; DLCO, diffusing capacity of lung for carbon monoGy, Gray; KPS, Karnofsky performance status; M, male; MI, myocardial infSUVmax, positron emission tomography-derived maximum standardized uptstereotactic body radiation therapy; T, tumor.
progression in the hilum or mediastinum. Distant failurewas defined as the presence of distant metastases onclinical examination or imaging. The primary outcomeswere local control and survival, which were measuredfrom the initiation of SBRT until death or last patientcontact. Local, nodal, and distant control and survivalestimates were calculated using Kaplan-Meier analysis.Statistical analyses were performed using StatView 5.0(SAS Institute, Cary, NC), and a P value less than .05 wasconsidered statistically significant.
Results
Patient No. 4 (see Fig 1) is a representative case in thepresent series. He is a 69-year-old male patient, withlongstanding chronic obstructive pulmonary disease whohad been undergoing yearly screening by CT scan fornodules first detected in 2005. In March 2009, a previouslynoted left upper lobe nodule increased in size from 8 mmto 14 mm. A PET-CT done at that time showed amaximum SUV of 2.8 for the nodule and no otherabnormalities. In May 2009, the patient underwent abronchoscopy with brushings of the lesion revealingSCLC. The workup was otherwise negative. A thoracicsurgeon deemed the patient medically inoperable becausehis forced expiratory volume in 1 second was 46% ofpredicted. Following a multidisciplinary thoracic assess-ment, SBRT was recommended and delivered as 60 Gy in3 fractions (per the Radiation Therapy Oncology Group
inoperable small cell lung cancer patients treated with SBRT
304 G.M.M. Videtic et al Practical Radiation Oncology: October-December 2013
0236 approach11), completed in June 2009. Four cycles ofcisplatin-etoposide were subsequently administered every3 weeks and completed in September 2009. PCI (25 Gy/10fractions) was completed November 2009. A completeresponse was achieved in the chest, with serial CT imagingrevealing disappearance of the tumor and evolving post-SBRT fibrotic response (Fig 1). The patient remains alive(as of May 2012), without evidence of disease.
Table 1 provides details on patient and tumorcharacteristics. In summary, the median Karnofskyperformance status was 80 (range, 50-90), the medianage was 68 years (range, 57-73), 4 patients were female,the median BMI was 27.55 (range, 20.1-31.9), and 1patient was still smoking at the time of treatment. Impairedpulmonary function was the reason for inoperability in 4
Figure 2 (A) Overall and (B) disease-free survival for 6medically inoperable early-stage small cell lung cancer patientstreated with stereotactic body radiation therapy (SBRT),chemotherapy, and prophylactic cranial irradiation. MST,median survival time.
cases. Median tumor size was 2.6 cm (range, 1.4-3.6). ByAmerican Joint Committee on Cancer criteria, 4 tumorswere T1 and 2 T2. One lesion was “central.” The medianPET-SUVmax for tumor was 9 (range, 2.8-21.1).
With respect to the specifics of individual treatment, 1patient had a mediastinoscopy. SBRT dose scheduleswere the following: 60 Gy/3 fractions (3 patients); 50Gy/5 fractions (2 patients); and 30 Gy/1 fraction (1patient). One patient received chemotherapy (CHT)before SBRT. One patient died of a brain aneurysmsoon after SBRT and never received either planned CHTor PCI. This patient was also 1 of the total 2 patients whodied before receiving PCI.
With respect to outcomes, median follow-up at thetime of analysis was 11.9 months. No grade 3 or highertoxicity was noted, with 1 grade 2 toxicity (chest wall).Figure 2 presents overall and disease-free survival curvesfor this series. Three patients were alive at analysis and 3had died of non-cancer causes, although 1 did havedistant disease at time of death. At 1 year, local controlwas 100%, there were no regional nodal failures, and 1patient developed distant failure in the form of livermetastases. Overall and disease-free survivals at 1 yearwere 63% and 75%, respectively.
Discussion
To our knowledge, this is the first reported seriesdescribing the utility of SBRT in the management ofmedically inoperable early-stage SCLC. Mindful of therarity of this disease presentation and the smallness of thispresent series, this report was intended to highlight newperspectives on expanding the range of the role of SBRT intreating lung cancer in selected high-risk patients.
First, it demonstrates that the same outcomes that havenow become expected with SBRT for medically inoper-able early-stage NSCLC; ie, feasibility, safety, excellentdisease control, minimal toxicity, and potential survivalbenefits,6 may be achievable for special presentations ofSCLC. Given the generic mechanisms by which radiationtherapy works combined with the recognized radiosen-sitivity of small cell disease, we hoped to produce at leastequivalent local control rates for SCLC from SBRT asseen for NSCLC. The local control rate of 100% seen forthis series supports this hypothesis, although werecognize that the number of patients is small and thefollow-up ongoing.
Second, as with the medically inoperable NSCLCpopulation, this study supports the utility of PET in stagingpatients specifically with respect to the mediastinum.Although the gold standard in lung cancer remainsmediastinoscopy, this procedure is rarely used in SBRTNSCLC patients given the fragility of this population, andclinical results to date suggest that regional nodal failure
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after PET staging prior to SBRT is b10%, with distantfailure predominating.6 This same pattern is now seen inthe current series of SCLC patients such that regionalnodal failure after SBRT was not seen for the 5 of 6patients who had no pathologic staging of the nodes. Thisseries also suggests that in the event of undetectable oroccult microscopic nodal disease, chemotherapy may besufficient to control the PET-negative mediastinum,without the need for radiation therapy.
Third, it suggests that the feasibility role of systemictherapy in vulnerable populations needs to be carefullystudied. Prospective randomized data do not in generalsupport the routine use of adjuvant platinum-basedchemotherapy for patients with resected stage I NSCLC.13
In the medically inoperable NSCLC population treatedwith SBRT, there has been even less expectation ofdefining a role for adjuvant chemotherapy since thepopulation has been generally judged too frail to tolerateconventional systemic therapies. However, since thedominant form of failure after SBRT, like surgery, appearsto be distant metastatic disease,6 there has been interest inexploring the possibility of adjuvant agents in selectedinoperable patients, especially with the advent of “tar-geted” or biologic therapies to mitigate toxicities. Incontrast, there has been routine use of adjuvant chemo-therapy in the setting of resected early-stage SCLC, basedon a number of historical series that have suggestedimprovements in survival when it is used.1 Likewise, PCIhas also been recommended for such patients because highrelapse rates in the brain have also been observed withpathologic stage I disease.1 The present series suggeststhat for some medically inoperable populations, curativesystemic therapies may be possible to administer and canbe tolerated by patients. Our observation has encouragedus to more actively investigate the role of adjuvanttherapies in properly selected medically inoperableNSCLC patients.
Fourth, a SBRT-based approach to stage I SCLCappears to have many advantages over the form ofconventional chemoradiation therapy used in limited-stage disease, especially with respect to toxicity. Radiationtherapy and chemotherapy are not given concurrently, thuspreventing additive toxicities. SBRT by definition in-volves no elective nodal irradiation and therefore does notproduce significant mediastinal or esophageal toxicity.Also, unlike conventional limited-stage radiation therapy,the timing of SBRT need not be linked to the initiation ofchemotherapy in order to still achieve excellent loco-regional control.
Lastly, among the most provocative findings pub-lished in the lung cancer SBRT literature have been theresults of Onishi et al,14 in which the survival of asubgroup of medically operable patients treated withSBRT was comparable with similar-stage patients treatedwith video-assisted thorascopic surgery or lobectomyand defining the role of SBRT in potentially operable
patients is becoming an active area of investigation. Aswith SBRT in NSCLC, it may be appropriate to considerthe utility of SBRT in operable early-stage SCLCpatients to mitigate surgery-related morbidity in orderto be able to transition more rapidly to the adjuvantchemotherapy and PCI required for improving survivalin this disease.
Conclusions
This novel case series suggests that SBRT for stage Imedically inoperable SCLC results in an excellent rate oflocal control, which is comparable with the data reportedfor medically inoperable early-stage NSCLC patientstreated with SBRT. Disease-specific survival is encourag-ing, and as with medically inoperable NSCLC patients,non-cancer comorbidities contribute significantly to mor-tality. The absence of regional nodal failure lends supportto the sole use of PET for characterizing the mediastinalnodes and suggests that radiation therapy is not needed tocontrol a PET-negative mediastinum. Administration ofplatinum-based CHT was feasible in this inoperable seriesand lends support to the possibility of adjuvant chemo-therapy in selected inoperable early-stage NSCLC patientsmanaged with SBRT.
References
1. Anraku M, Waddell TK. Surgery for small-cell lung cancer. SeminThorac Cardiovasc Surg. 2006;18:211-216.
2. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared withonce-daily thoracic radiotherapy in limited small-cell lung cancertreated concurrently with cisplatin and etoposide. N Engl J Med.1999;340:265-271.
3. Urschel JD. Surgical treatment of peripheral small cell lung cancer.Chest Surg Clin N Am. 1997;7:95-103.
4. Dusmet M, Goldstraw P. Surgery for small cell lung cancer. HematolOncol Clin North Am. 2004;18:323-341.
5. Little AG, Rusch VW, Bonner JA, et al. Patterns of surgical care oflung cancer patients. Ann Thorac Surg. 2005;80:2051-2056.
6. Videtic GM, Stephans KL. The role of stereotactic body radiotherapyin the management of non-small cell lung cancer: an emergingstandard for the medically inoperable patient? Curr Oncol Rep.2010;12:235-241.
8. Stephans KL, Djemil T, Reddy CA, et al. A comparison of twostereotactic body radiation fractionation schedules for medicallyinoperable stage I non-small cell lung cancer: the Cleveland Clinicexperience. J Thorac Oncol. 2009;4:976-982.
9. Videtic GM, Stephans K, Reddy C, et al. Intensity-modulatedradiotherapy-based stereotactic body radiotherapy for medicallyinoperable early-stage lung cancer: excellent local control. Int JRadiat Oncol Biol Phys. 2010;77:344-349.
10. Stephans KL, Djemil T, Reddy CA, et al. Comprehensive analysis ofpulmonary function test (PFT) changes after stereotactic bodyradiotherapy (SBRT) for stage I lung cancer in medically inoperablepatients. J Thorac Oncol. 2009;4:838-844.
306 G.M.M. Videtic et al Practical Radiation Oncology: October-December 2013
11. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiationtherapy for inoperable early stage lung cancer. JAMA. 2010;303:1070-1076.
12. Common Terminology Criteria for Adverse Events v3.0 (CTCAE).Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed February 13,2012.
13. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatinevaluation: a pooled analysis by the LACE Collaborative Group. JClin Oncol. 2008;26:3552-3559.
14. Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotacticradiotherapy (HypoFXSRT) for stage I non-small cell lung cancer:updated results of 257 patients in a Japanese multi institutional study.J Thorac Oncol. 2007;2(7 Suppl 3):S94-S100.
